An integrated physiology-based model for the interaction of RAA system biomarkers with drugs.

The renin angiotensin aldosterone system (RAAS) is a paramount target for the pharmacological treatment of cardiovascular diseases. As modeling and simulation techniques are becoming increasingly utilized in cardiovascular research, our aim was to develop a physiology-based model that describes the effect of different drugs at different doses on the RAAS and integrates physiology-based description drug pharmacokinetics (PK). First, a basic RAAS model was developed in which equations for drug effects were included and missing parameters estimated. Next, a physiology-based PK model for enalapril and enalaprilat was developed and coupled to the RAAS model. Simulation of the effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aliskiren administration on angiotensins I and II did not reveal significant overestimation or underestimation. For all drugs, the error numerics were acceptable. The model also encompassed the PK of intravenous and oral enalapril and its conversion to enalaprilat. In summary, we report a physiology-based model for the interaction of the RAAS biomarkers angiotensin I and II with enalapril, benazepril, aliskiren, and losartan that allows for an adequate description of the RAAS response after single administration of the drugs. Such a comprehensive description may lead to a better understanding of the effects of pharmacological interventions in the RAAS.